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Last updated: 9/26/2024
Years published: 2022
NORD gratefully acknowledges Gregory Cichon, MD candidate, Creighton School of Medicine and Lois J. Starr, MD, PhD, FAAP, FACMG University of Nebraska Medical Center, for the preparation of this report.
Summary
Loeys-Dietz syndrome (LDS) is a genetic condition affecting the connective tissue and involving multiple organ systems including the blood vessels, skeleton, eyes and skin. It was first described in 2005 and has many shared characteristics with Marfan syndrome. While not all individuals have characteristic craniofacial features, individuals with this disorder often have widely spaced eyes, tortuous blood vessels, a uvula that splits in two (bifid uvula) and/or cleft palate.
LDS is an autosomal dominant genetic condition that can be inherited from a parent or occur for the first time in an individual as a result of a new pathogenic variant in one of several genes: GFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3.
There is still no cure for LDS. Treatment focuses on managing the specific symptoms.
Introduction
People with LDS are at risk for blood vessel aneurysms, particularly at the root of the aorta, but also in other locations of the arterial tree, that can be life-threatening. Therefore, it is extremely important to screen, diagnose, and prevent complications early.
Loeys-Dietz syndrome (LDS) is a connective tissue disorder that affects the bones, ligaments, arterial walls and skin. The symptoms can vary widely, and a person with LDS may only have a few of the following signs or symptoms but still have the condition:
Common signs and symptoms may include:
People with LDS are at risk for serious complications like ruptured aneurysms, so early detection and management are critical.
Loeys-Dietz syndrome (LDS) was first described relatively recently (2005) and is a rare disease. More research is needed to fully understand the causes of LDS. Researchers have identified several genes in the transforming growth factor beta (TGFฮฒ) pathway which may be altered in the disease including: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, and TGFB3. The genes in this pathway are important for gene expression, cell growth, differentiation and controlled cell death (apoptosis). Notably, the gene SMAD3 has been associated with a condition known as aneurysm-osteoarthritis syndrome (AOS), which shares some of the characteristics of LDS. Disease-causing changes (pathogenic variants) in all of these genes cause them to lose their normal function, resulting in many of the symptoms of LDS.
About 1/3 of people affected with LDS have an affected parent, while 2/3 of patients have a new or de novo pathogenic gene variant. These variants may then be passed down to children in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
LDS is a rare disorder that affects males and females in equal numbers. The prevalence of LDS is unknown but estimated to be 1:50,000. More than 1,000 families with LDS have been described in the literature until 2018. Though with more availability of genetic testing the number of patients diagnosed has increased significantly in recent years. The condition occurs in all ethnic groups.
The diagnosis of LDS is based on clinical suspicion and molecular confirmation through genetic testing to look for pathogenic variants in the causal genes: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB, and TGFB3. Genetic testing should be considered in patients with typical signs/symptoms described previously and in families with known histories of thoracic aortic aneurysms. Cleft palate/bifid uvula, widely spaced eyes, translucent skin, arthritis and/or arterial tortuosity or aneurysm should prompt a physician to consider testing for LDS.
Prenatal diagnosis by genetic testing is possible for pregnancies at increased risk for LDS if the disease-causing variant in the family is already known.
There is no known cure for LDS, but there are treatments directed at specific symptoms. These treatments typically require a team of specialists including a geneticist, cardiologist, heart (cardiothoracic) and bone (orthopedic) surgeons, rheumatologist, among others.
Most importantly, the goal of treatment is to screen and correct blood vessel weaknesses before they tear. The physician may prescribe a beta- or angiotensin receptor blocker such as losartan to slow down the ballooning/stretching of the aortic root. Every 6 months to 1 year, the individual should be screened for aneurysms of the entire arterial tree (from head to hips). This screening includes blood vessel imaging by CT angiography or MR angiography and heart imaging by echocardiography. If repeated imaging does not show any changes or concern for aneurysms, it may be acceptable to image less frequently. The doctors will be looking to see whether the aortic root balloons to larger than 4 cm (1.5 inches), at which point they may recommend surgery to replace the ballooning section of the aorta and sometimes the aortic valve of the heart. This surgery is typically safe and effective in fixing the problem.
To treat some of the musculoskeletal abnormalities associated with LDS, the care team may recommend nonsurgical management of the symptoms such as bracing or surgical correction of the abnormalities. These abnormalities include an abnormally curved spine (scoliosis), an indented or protruding chest, and issues with the bones of the neck. Doctors will recommend X-rays and CT scans to determine whether surgery should be performed. These surgeries can be complicated and require close attention for complications afterwards.
Staying active and conditioned is recommended for individuals with LDS. Athletic goals and limits should be discussed with the cardiologist and the care team to determine an individualized health plan.
The relationship between different variants in genes that cause LDS and specific physical characteristics is being studied to improve clinical and surgical recommendations.
Clinical trials around the world are investigating which drugs are best to slow the growth of the aortic root and which surgeries are the most effective for individuals with LDS.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Iqbal R, Alom S, BinSaeid J, Harky A. Loeys-Dietz syndrome pathology and aspects of cardiovascular management: A systematic review. Vascular. 2021 Feb;29(1):3-14. doi: 10.1177/1708538120934582. Epub 2020 Jun 19. PMID: 32559129.
Lynch CP, Patel M, Seeley AH, Seeley MA. Orthopaedic management of Loeys-Dietz syndrome: a systematic review. J Am Acad Orthop Surg Glob Res Rev. 2021 Nov 15;5(11):e21.00087. doi: 10.5435/JAAOSGlobal-D-21-00087. PMID: 34779796; PMCID: PMC8594655.
Velchev JD, Van Laer L, Luyckx I, Dietz H, Loeys B. Loeys-Dietz syndrome. In: Halper, J. (eds) Progress in Heritable Soft Connective Tissue Diseases. Advances in Experimental Medicine and Biology 2021;1348: 251โ264. https://doi.org/10.1007/978-3-030-80614-9_11
Fuhrhop SK, McElroy MJ, Dietz HC 3rd, et al. High prevalence of cervical deformity and instability requires surveillance in Loeys-Dietz syndrome. J Bone Joint Surg Am 2015; 97:411.
Groenink M, den Hartog AW, Franken R, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J 2013; 34:3491.
Brooke BS, Habashi JP, Judge DP, et al. Angiotensin II blockade and aortic-root dilation in Marfanโs syndrome. N Engl J Med 2008; 358:2787.
LeMaire SA, Pannu H, Tran-Fadulu V, Carter SA, Coselli JS, Milewicz DM. Severe aortic and arterial aneurysms associated with a TGFBR2 mutation. Nat Clin Pract Cardiovasc Med. 2007 Mar;4(3):167-71. doi: 10.1038/ncpcardio0797. PMID: 17330129; PMCID: PMC2561071.
Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006; 312:117.
Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24;355(8):788-98. doi: 10.1056/NEJMoa055695. PMID: 16928994.
Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005 Mar;37(3):275-81. doi: 10.1038/ng1511. Epub 2005 Jan 30. PMID: 15731757.
INTERNET
Wright MJ, Heidi MC. Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders. UpToDate. 28 Apr. 2022. https://www.uptodate.com/contents/genetics-clinical-features-and-diagnosis-of-marfan-syndrome-and-related-disorders Accessed Sept 27, 2022.
Dietz H. FBN1-Related Marfan Syndrome. 2001 Apr 18 [Updated 2022 Feb 17]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1335/ Accessed Sept 27, 2022.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
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